Oldenlandia diffusa suppresses metastatic potential through inhibiting matrix metalloproteinase-9 and intercellular adhesion molecule-1 expression via p38 and ERK1/2 MAPK pathways and induces apoptosis in human breast cancer MCF-7 cells

• Published in: Journal of ethnopharmacology Vol. 195; pp. 309 - 317
• Main Authors: Chung, Tae-Wook, Choi, Hyunju, Lee, Ji-Min, Ha, Sun-Hyung, Kwak, Choong-Hwan, Abekura, Fukushi, Park, Jun-Young, Chang, Young-Chae, Ha, Ki-Tae, Cho, Seung-Hak, Chang, Hyeun Wook, Lee, Young-Choon, Kim, Cheorl-Ho
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 04.01.2017
• Subjects: Antineoplastic Agents, Phytogenic - isolation & purification; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; Breast Neoplasms - drug therapy; Breast Neoplasms - enzymology; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Butanols - chemistry; Cell Movement - drug effects; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Enzyme Activation; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; ICAM-1; Intercellular Adhesion Molecule-1 - genetics; Intercellular Adhesion Molecule-1 - metabolism; Matrix Metalloproteinase 9 - metabolism; MCF-7 Cells; Methanol - chemistry; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; MMP-9; Neoplasm Invasiveness; Neoplasm Metastasis; NF-kappa B - metabolism; Oldenlandia - chemistry; Oldenlandia diffusa; Oleanolic acid (PubChem CID: 10494); p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Phytotherapy; Plant Extracts - isolation & purification; Plant Extracts - pharmacology; Plants, Medicinal; Signal Transduction - drug effects; Ssperuloside, E-6-O-p-coumaroyl scandoside methyl ester and E-6-O-p-coumaroyl scandoside methyl ester-10-methyl ether (PubChem CID: 84298); Stigmasterol (PubChem CID: 5280794); Transcription, Genetic - drug effects; Transfection; Ursolic acid (PubChem CID: 64945); Water - chemistry; Oleanolic acid (PubChem CID: 10494); MOD; PMA; Stigmasterol (PubChem CID: 5280794); Ssperuloside, E-6-O-p-coumaroyl scandoside methyl ester and E-6-O-p-coumaroyl scandoside methyl ester-10-methyl ether (PubChem CID: 84298); HRP; Ursolic acid (PubChem CID: 64945); MCF-7 cells; ICAM-1; PARP; ECM; MMP; TBS-T; OD; BOD; FBS; Oldenlandia diffusa; MMP-9; Apoptosis
• ISSN: 0378-8741; 1872-7573
• DOI: 10.1016/j.jep.2016.11.036

Oldenlandia diffusa (OD) has long been known as an apoptotic inducer in breast tumors in ethnomedicine. To scientifically confirm the anti-breast cancer effects of water, methanol (MeOH) and butanol (BuOH) extracts of O. diffusa on cell apoptosis, matrix metalloproteinases (MMPs), intercellular adhesion molecule (ICAM)−1 and intracellular signaling in MCF-7 breast cancer cells. MeOH extracts (MOD) and BuOH extracts (BOD) were prepared and examined for their ability to inhibit phorbol myristate acetate (PMA)-induced matrix metalloproteinase (MMP)−9 and intercellular adhesion molecule (ICAM)−1 expressions in MCF-7 human breast cancer cells. Additionally, transwell migration, invasion and transcriptional activity were assessed. Results of immunofluorescence confocal microscopy for translocation of NF-κB and p-ERK and p-p38 were also checked. Finally, apoptotic signals including processed caspase-8, caspase-7, poly ADP-ribose polymerase, Bax and Bcl-2 were examined. MOD and BOD specifically inhibited PMA-induced MMP-9 expression as well as invasive and migration potential via ICAM-1. The inhibitory activity was also based on the suppressed transcriptional activity in MCF-7 breast cancer cells. Results of immunofluorescence confocal microscopy showed that translocation of NF-κB decreased upon BOD and MOD treatments, with a decreased level of p-ERK and p-p38 phosphorylation. In addition, treatment of MCF-7 cells with MOD and BOD activated apoptosis-linked proteins including enzymatically active forms of processed caspase-8, caspase-7 and poly ADP-ribose polymerase, together with increased expression of mitochondrial apoptotic protein, Bax and decreased expression of Bcl-2. The results indicate that OD as an anti-metastatic agent suppresses the metastatic response by targeting p-ERK, p-38 and NF-κB, thus reducing the invasion capacity of MCF-7 breast cancer cells through inhibition of MMP-9 and ICAM-1 expression and plays an important role in the regulation of breast cancer cell apoptosis. [Display omitted]